Some of the compounds of Formulae I and II are generally useful as anti-cancer, anti-obesity, anti-diabetic, anti-coronary agents, anti-aging agents, anti-hypolipidemic agents and anti-autoimmune agents. (Schwartz et. al., U.S. Pat. Nos. 5,656,621; 4,898,694; 5001119, 5028631; 5157031, 5696106; 5,700,793; 5,714,481, 5,804,576). In particular, 16α-fluoro-5-androsten-17-one (fluasterone) has been shown to have reduced androgenic effects while maintaining the therapeutic effects in comparison to dehydroepiandrosterone (DHEA). (McCormick et. al., Carcinogenesis 2007 28(2):398-403). Fluasterone has been shown to improve recovery from traumatic brain injury in rat model of traumatic brain injury. (Malik et. al. Journal of Neurotrauma 20:463-476, 2003). Furthermore, Fluasterone is also known to inhibit collagen-induced arthritis in mice, indicating efficacy against rheumatoid arthritis. (Offfier et. al, Clinical Immunology, 110(2), 2004, 181-190; Williams J. R. et. al., Methods in Molecular Medicine, 2004, 98, 207-216). Fluasterone treatment inhibits the acute inflammatory and hyperplastic effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) induced skin papilloma formation. (Schwartz et. al. Cancer Res. 48:4817 4822, 1988; Schwartz et. al., Carcinogenesis 10:1809-1813, 1989; Pashko et. al. Carcinogenesis 12:2189-2192, 1991; Hastings et. al., Carcinogenesis 9:1099-102, 1988).
Problems associated with steroidal compositions include the androgenicity and poor oral availability associated with them. For example, clinical trials with DHEA are encumbered by the high oral doses required as well as the conversion of DHEA into active androgens. The use of less androgenic congeners as well as non-oral formulations may facilitate testing of this class of compounds. (Schwartz et. al., Ageing Research Reviews, 3(2), 2004, 171-187. The formulations herein address solubility problems associated with insoluble pharmaceutical agents, and allows the preparation of topical formulations of compositions with low androgenicity.
Compounds of Formula I and II are useful against a wide variety of diseases, including cancer, diabetes and metabolic syndrome. For example, fluasterone due to its reduced androgenic effect would be useful for chemoprevention.
Glucocorticoids are a widely used class of steroid hormones, but are associated with significant side effects. Glucocorticoids are characterized by an ability to bind with the glucocorticoid receptor. (Thomas et. al., U.S. Patent Publication No. 20060069071). Topical glucocorticoids are well known to cause local skin atrophy (thinning of the skin), purpura (bruised-appearing skin), striae (“stretch marks”), tolerance and “addiction syndrome”. Combined dehydroepiandrosterone-glucocorticoid compositions have been described as effective pharmaceutical treatments for dermatitis. (Thomas et. al., WO2006/036484). Furthermore, DHEA is known to have antiglucocorticoid effects in the brain. (R. Morfin, DHEA and the brain, Wiley, 2002, 52-53). However, DHEA is known to have androgenic side effects. As such, it would be advantageous to have compositions with reduced androgenicity to reduce side effects associated with glucocorticoids.
Inhibition of G6PDH was believed to be a critical mechanism by which DHEA and DHEA analogs reduce inflammation and oxygen free radical formation. (Schwartz et. al., Ageing Res. Reviews. 3:171-187, 2004). The effectiveness of fluasterone against TPA-induced skin papilloma formation was believed to be mediated by the inhibition of glucose 6-phosphate dehydrogenase (G6PDH) with a consequent lowering of NADPH levels and reactive oxygen formation. (Schwartz et. al., Cancer Lett. 168:7-14, 2001). Without being bound by any mechanism, the data herein indicate that G6PDH inhibition may not be the mechanism by which these steroids produce an anti-glucocorticoid effect. Compound 8356 (16α-fluoro-5α-androstan-17-one) is a more potent G6PDH inhibitor than fluasterone yet it is about ⅛ as active in protecting against dexamethasone. (Schwartz et. al., Cancer Res., 48:4817 4822, 1988). However, due to poor water solubility oral bioavailability of fluasterone has required very high dosage levels. Nanosized fluasterone formulations were shown to have better bioavailability than unmilled and micronized formulations. (Janjikhel, et. al., AAPS Annual Meeting Abstracts, 2002). Even nanosized formulations required very high dosages (100 mg/kg) for oral delivery.
Thus, fluasterone is difficult to formulate, particularly for topical administration, due at least in part, to its very low water solubility. Therefore, a need exists to provide new formulations for the administration of fluasterone.